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32 Cards in this Set

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Define: metabolism
Reduce the duration of action of drugs - inactive form of less active metabolite
Define: excretion
Urine, feces, expired air, saliva, sweat, breast milk
How does codeine become morphine?
Lipophilic drugs gets transformed to more polar drugs (CYP2D6)
What organs is most important in first-pass effect?
liver
What happens in phase I reaction?
Enhance POLARITY by introducing/unmasking a functional group (OH, NH2, SH); IRREVERSIBLE reaction; Metabolite = inactivated or enhanced; If polar enough can be readily excreted
What happens in a Phase II reaction
Phase I conjugation that reacts with (glucuronic acid, sulfuric acid, acetic acid, amino acid); REVERSIBLE; products become highly polar -> easily excreted
What are the reactions in Phase I? Phase II?
Phase I = Oxidation, reduction, deamination, hydrolyses, Phase II = conjugation
What is the MOA for metabolism of Isoniazid?
Phase II (acetylation)-> Phase I (hydrolysisi)
Mixed function oxidases
Aka mono-oxygenases in the smooth ER; able to do oxidation-reduction reaction; requires P450 to do its job
What is the output of cytochrome P450?
Activated oxygen (potent oxidizer); Function = low substrate specificity + highly lipid soluble
What CYPs are the major Cytochrome P450?
1. CYP3A4, 2. CYP2C9, 3. CYP1A2, 4. CYP2D6
What is induction?
↑ ability of an enzyme - occurs b/c 1. could b on two different drugs -> thus ↑ number of metabolites in system and not enough drug -> could lead to drug tolerance
What is a problem of induction?
May lead to tolerance, results in ↓ pharacological action of inducer and co-administered drugs, reactive metabolites may exacerbate metabolite-induced toxicity
For omeprazole and smoking what CYP450 system does it induce? What drugs have a built up tolerance?
CYP450 = 1A2, Tolerance = Acetaminophen, Tamoxifen
For barbiturates (nembutal) what CYP450 system does it induce? What drugs have a built up tolerance?
CYP450 = 2C9; tolerance = celecoxib, Losartan
For macrolides and stJohns wort what CYP450 system does it induce? What drugs have a built up tolerance?
CYP450 = 3A4; Tolearance = Diazepam, spironolactone
Define: inhibition
Ceertain durgs inhibit P450 - reducing metabolism of the inhibitor or other substrates
Fluvoxamine inhibits what CYP450? What drugs have a decreased metabolism?
CYP = 1A2, ↓ metabolism = Acetaminophen + tamoxifen (receives longer response)
Paroxetine inhibits what CYP450? What drugs have a ↓ metabolism?
CYP = 2D6, ↓ metabolism = codeine + metoprolol (receives longer response)
Erythromycin + grapefruit juice inhibits what CYP450? What drugs have a ↓ metabolism?
CYP = 3A4, ↓ metabolism = diazepam + spironolactone (receives longer response)
What are the Phase I enzymes?
1. Flavin monooxygenase, 2. amine oxidases, 3. dehydrogenations (alcohol dehydrogenase)
What is the location of Phase II reactions
Microsomes or cytosol
What is the name of transferase needed for Phase II glucuronidation reaction? Example of a drug that uses this?
Transferase = UGTs (microsomes); Drug Example = Digoxin
What is the name of transferase needed for Phase II ACETYLATION reaction? Example of a drug that uses this?
Transferase = NATs(cytosol); Drug example = Isoniazid
What is the name of transferase needed for Phase II GLUTATHIONE reaction? Example of a drug that uses this?
Transferase = GST (Cytosol, microsomes); Drug example = Acetaminophen
What is the name of transferase needed for Phase II GLYCINE reaction? Example of a drug that uses this?
Transferase = Acyl-CoA glycinetransferase (mitochondria); Drug Example = Nicotinic acid
What is the name of transferase needed for Phase II SULFATION reaction? Example of a drug that uses this?
Transferase = SULTs (cytosol); Drug example = acetaminophen
What is the name of transferase needed for Phase II METHYLATION reaction? Example of a drug that uses this?
Transferase = TMTs (cytosol); Drug example = Dopamine
What drug is given to prevent toxic metabolites from acetominophen?
N-acetylcysteine = prevents acetaminophen to under go P450-dependent GSH-conjugation pathway (toxic metabolites)
What are some factors the influence drug metabolism?
1. Age, 2. gender, 3. liver function (cirrhosis, hepatitis), 4. cardiovascular (limited blood flow), 5. cruciferous veggies (broccoli/cabbage), 5. charcoal-broiled food, cigarette smoke, pesticides
What are some genetic factors that influence drug metabolism?
1. Fast vs slow acetylators (isoniazid), 2. ultra-rapid metabolizers (CYP2D6 is too good thus need more drug for same response), 3. poor metabolizers - side effect occur more readily (d/t impaired drug clearance)
Metabolism of acetaminophen
1. Glucuronidation + sulfination (95%- normal safe metabolism), 2. P450-depenent GSH conjugation pathway (5% - generates ROS -> liver cell death)